Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by Anticancer Therapies in the Era of Checkpoint Inhibitors

Abstract

IMPORTANCEAlthough typically impressive, objective responses to immune checkpoint inhibitors (ICIs) occur in only 12.5% of patients with advanced cancer. The majority of patients do not respond due to cell-intrinsic resistance mechanisms, including human leukocyte antigen (HLA) class I antigen-processing machinery (APM) defects. The APM defects, which have a negative effect on neoantigen presentation to cytotoxic T lymphocytes (CTLs), are present in the majority of malignant tumors. These defects are caused by gene variations in less than 25% of cases and by dysregulated signaling and/or epigenetic changes in most of the remaining cases, making them frequently correctable. This narrative review summarizes the growing clinical evidence that chemotherapy, targeted therapies, and, to a lesser extent, radiotherapy can correct HLA class I APM defects in cancer cells and improve responses to ICIs.OBSERVATIONS Most chemotherapeutics enhance HLA class I APM component expression and function in cancer cells, tumor CTL infiltration, and responses to ICIs in preclinical and clinical models. Despite preclinical evidence, radiotherapy does not appear to upregulate HLA class I expression in patients and does not enhance the efficacy of ICIs in clinical settings. The latter findings underscore the need to optimize the dose and schedule of radiation and timing of ICI administration to maximize their immunogenic synergy. By increasing DNA and chromatin accessibility, epigenetic agents (histone deacetylase inhibitors, DNA methyltransferase inhibitors, and EZH2 inhibitors) enhance HLA class I APM component expression and function in many cancer types, a crucial contributor to their synergy with ICIs in patients. Furthermore, epidermal growth factor receptor (EGFR) inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors are effective at upregulating HLA class I expression in EGFR-and BRAF-variant tumors, respectively; these changes may contribute to the clinical responses induced by these inhibitors in combination with ICIs.CONCLUSIONS AND RELEVANCE This narrative review summarizes evidence indicating that chemotherapy and targeted therapies are effective at enhancing HLA class I APM component expression and function in cancer cells. The resulting increased immunogenicity and recognition and elimination of cancer cells by cognate CTLs contributes to the antitumor activity of these therapies as well as to their synergy with ICIs.

Identification of Survival Risk and Immune-Related Characteristics of Kidney Renal Clear Cell Carcinoma

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Identification of Immune-Related Subtypes and Construction of a Novel Prognostic Model for Bladder Urothelial Cancer

“…In comparison to Immunity_L, there was lower TumorPurity, higher fractions of immune cells, higher HLA gene expression, and richer immune-related pathways in Immunity_H, suggesting that the immunogenicity of Immunity_H was stronger, and revealing a potential relationship between immunogenicity and TumorPurity in BLCA. Studies have shown that HLA genes exert a momentous function in the recognition of cancer cells and in antitumor activity [ 31 , 32 ]. Activation of immune cells also plays an important role in the elimination of tumor cells [ 33 , 34 ].…”

Chaperones and Catalysts: How Antigen Presentation Pathways Cope With Biological Necessity

“…The importance of understanding the mechanistic details of peptide loading of MHC I molecules, not only with respect to the obvious applied utility of appreciating the cellular evolution of immunevasion in tumorigenesis ( 60 – 62 ), but also with respect to appreciating the interplay between basic aspects of the protein folding problem, peptide loading, and structure prediction cannot be overemphasized. In this brief review we highlight how structural information—derived both experimentally and computationally—complements our understanding of fundamental aspects of immune function.…”